Viral Oncoproteins as Probes for Tumor Suppressor Function (original) (raw)
Oncogenes and Tumor Suppressor Genes
Acta Oncologica, 1988
The artificial selection of the directly acting or acute RNA tumor viruses for high transforming ability has led to the isolation of defective retroviral genomes that have picked up, by accidental recombination, some of the important genes that influence, trigger or regulate cell division. These genes belong to at least four functionally different groups. Each of them can contribute to tumor development and/or progression after activation by structural or regulatory changes. Growth factor genes may act as oncogenes following constitutive activation in a cell that normally responds to, but does not produce, the corresponding growth factor (the autocrine model, exemplified by sis). Growth factor receptors may be fixed in a state of continuous, faulty signalling by the truncation of their external, ligand binding portion (examples: erb-B, fms). Genes coding for proteins involved in signal transduction may be activated by point mutations in certain, important domains (example: the ras-family). DNA binding proteins, presumably involved in DNA replication may drive cell division after constitutive activation by retroviral insertion, chromosomal translocation or gene amplification (example: the mycfamily).
Molecular Mechanisms Associated with Virus-induced Oncogenesis and Oncolysis
Cancer Research Journal
Cancer is a leading cause of human deaths worldwide. Besides inherited genetic disorders, a diverse range of physical, chemical and biological agents may induce cancer. About 15-20% of cancers are known to be originated due to pathogens. Viruses are considered to be the second (after smoking) most important risk factor in inducing human cancer. Viruses may either harbour a copy of oncogene or have an ability to alter the expression of cellular copy of the oncogenes. Both RNA and DNA viruses are can induce oncogenesis. Most of the DNA tumour viruses either integrate their genome (complete or part of it) into the host genome or express early genes that are required for early event of virus replication. These early genes are responsible for oncogenic transformation of host cells. Based upon the mechanism involved, oncogenic RNA viruses are divided into two groups-transforming and non-transforming RNA viruses. Transforming RNA viruses carry viral oncogenes that are homologous to the host oncogene, their expression in infected cells results in oncogenic transformation of the cell. Non-transforming RNA viruses induce oncogenesis similar to the DNA viruses. Contrary, oncolytic viruses selectively replicate in cancerous cells and induce cell death without any damage to the normal tissues. Typically, oncolytic viruses are nonpathogenic to humans that can naturally replicate in cancer cells by exploiting oncogenic cell signalling pathways. Pathogenic viruses can also be genetically manipulated which allow them to replicate in cancerous but not in normal cells. This review review describes the molecular mechanisms associated with virus induced oncogenesis and oncolysis.
Oncogene, 2010
Replication-competent oncolytic viruses hold great potential for the clinical treatment of many cancers. Importantly, many oncolytic virus candidates, such as reovirus and myxoma virus, preferentially infect cancer cells bearing abnormal cellular signaling pathways. Reovirus and myxoma virus are highly responsive to activated Ras and Akt signaling pathways, respectively, for their specificity for viral oncolysis. However, considering the complexity of cancer cell populations, it is possible that other tumorspecific signaling pathways may also contribute to viral discrimination between normal versus cancer cells. Because carcinogenesis is a multistep process involving the accumulation of both oncogene activations and the inactivation of tumor suppressor genes, we speculated that not only oncogenes but also tumor suppressor genes may have an important role in determining the tropism of these viruses for cancer cells. It has been previously shown that many cellular tumor suppressor genes, such as p53, ATM and Rb, are important for maintaining genomic stability; dysfunction of these tumor suppressors may disrupt intact cellular antiviral activity due to the accumulation of genomic instability or due to interference with apoptotic signaling. Therefore, we speculated that cells with dysfunctional tumor suppressors may display enhanced susceptibility to challenge with these oncolytic viruses, as previously seen with adenovirus. We report here that both reovirus and myxoma virus preferentially infect cancer cells bearing dysfunctional or deleted p53, ATM and Rb tumor suppressor genes compared to cells retaining normal counterparts of these genes. Thus, oncolysis by these viruses may be influenced by both oncogenic activation and tumor suppressor status.
Viral oncoprotein binding to pRB, p107, p130, and p300
Virus Research, 1995
The purpose of this review is to bring attention to some additional work in the tumor virus/ tumor suppressor field which may have been overshadowed by reports describing adenovirus, SV40, and HPV oncoprotein binding to pRB and ~53. The data reviewed herein provide further support for the model that a common mechanism by which DNA tumor viruses transform cells involves inactivation of cellular proteins which function as negative regulators of cell growth.
Human oncogenic viruses and cancer
The role of viral infection in cancer was established towards the beginning of 20th century. The study of tumour viruses, their oncogenes and different mechanisms employed by these viruses to subvert the growth-suppressive and pro-apoptotic functions of host tumour suppressor genes has laid the foundation of cancer biology. The human tumour viruses induce malignancies after a prolonged latency and in conjunction with other environmental and host factors. The eight known human tumour viruses contribute to nearly 10–15% of the cancers worldwide. Advancements in research on virus-related cancers offer a plethora of opportunities to fight cancer by preventing viral spread through vaccination and use of antivirals. Besides, recent developments on viral oncogenic mechanisms should allow development of novel and targeted approaches for control and treatment of virus-associated human cancers.
Effect of Transforming Viruses on Molecular Mechanisms Associated With Cancer
Journal of Cellular Physiology, 2008
Viruses have been linked to approximately 20% of all human tumors worldwide. These transforming viruses encode viral oncoproteins that interact with cellular proteins to enhance viral replication. The transcriptional and post-transcriptional effects of these viral oncoproteins ultimately result in cellular transformation. Historically, viral research has been vital to the discovery of oncogenes and tumor suppressors with more current research aiding in unraveling some mechanisms of carcinogenesis. Interestingly, since transforming viruses affect some of the same pathways that are dysregulated in human cancers, their study enhances our understanding of the multistep process of tumorigenesis. This review will examine the cellular mechanisms targeted by oncogenic human viruses and the processes by which these effects contribute to transformation. In particular, we will focus on three transforming viruses, human T-cell leukemia virus type-I, hepatitis B virus and human papillomavirus. These viruses all encode specific oncogenes that promote cell cycle progression, inhibit DNA damage checkpoint responses and prevent programmed cell death in an effort to promote viral propagation. While the transforming properties of these viruses are probably unintended consequences of replication strategies, they provide excellent systems in which to study cancer development.
A Review on Gene Involved in Cancer Development and Oncogenic Viruses
2015
Oncogenic viruses are the viruses that cause cancers in their natural hosts or experimental animal systems which are thought to be causative agents of about 15-20% of cancers. They have been broadly classified into the DNA oncogenic viruses and RNA oncogenic viruses based on the nature of the nucleic acid contain within their virion. The oncogenic DNA and RNA viruses that have been identified both in animals and humans includes retroviruses, papillomaviruses, herpesviruses and other DNA viruses. Oncogenic viruses promote cellular transformation, prompt uncontrollable cell generation and lead to development of malignant tumors. Virtually all type of normal cells may undergo the changes that eventually create tumors. For better understanding of cancer, knowing the mechanisms through which cancers produced is important. Generally this paper gives highlight about some of the gens induced cancer and related oncogenic viruses.
Oncogenic viruses: DUBbing their way to cancer
Ubiquitination is one of the most important post-translational modifications of proteins with a profound effect on their intracellular stability and activity. Deubiquitinases (DUBs), on the other hand, act by removing the ubiquitin moiety from proteins and thereby reverse their stability and/or activity. Besides, DUBs play a major role in maintenance of free ubiquitin pool, histone modification, vesicular trafficking and receptor recycling. The revelation of DUB interactome by Sowa et al., [1] highlighted the importance of DUBs in key cellular pathways. While the role of E3 ubiquitin ligases in the virus biology is well documented, the involvement of DUBs in viral life cycle is still being probed. Recent findings suggest DUBs could play a central role in invasion and pathogenesis of oncogenic viruses. Viral oncoproteins such as E6 and E7 of human papilloma virus and Tax of human T-cell leukemia virus type 1 are now known to target cellular DUBs such as cyclindromatosis tumor suppressor, ubiquitin-specific proteases 7, 11, 15 and 20, A-20 and signal-transducing adaptor molecule binding protein-like-1 in order to improve their intracellular stability and/or subjugate cellular signaling pathways. The viral oncoprotein-DUB interactions create an ambience leading to unbridled proliferation of virus-infected cells and drive cell transformation. Interestingly, some viruses like herpes simplex virus-1, Epstein-Barr virus, human cytomegalovirus and Kaposi’s Sarcoma-associated herpes virus also encode their own DUBs such as UL36, UL48, BPLF1 and ORF64 to support viral invasion, replication, and persistence and even subvert host immune responses. Efforts are also underway to find specific inhibitors that can abrogate the interaction between cellular DUB and viral oncoproteins or inhibit viral DUBs as this might result in the development of next generation cancer chemotherapeutic agents. This review showcases the relevance of the viral DUBs and the cellular DUBs with interacting viral partners in virus-triggered cancer development. Keywords: Deubiquitinase, interactome, oncogenic viruses, ubiquitination, ubiquitin proteasome system
Cellular onc genes: their role as progenitors of viral onc genes and their expression in human cells
Haematology and blood transfusion, 1983
Viral transforming (v-onc) genes are derived from cellular (c-onc) genes that are highly conserved among vertebrates. Comparative studies of v-onc and c-onc genes have shed some light on the mechanism leading to formation of the transforming viruses. A specific example of the sis gene is presented here for illustration. Studies on the expression of six c-onc genes in human cells revealed at least three categories of onc genes: (a) those that are universally expressed and probably are important in basic cellular functions, (b) those that are not detectably expressed in the cells examined and may have very transient expression in development, and (c) those that are only expressed in specific cell types and may be important in tissue differentiation. Our studies do not show conclusively a role of these onc genes in human neoplasias.
ONCOVIRUSES AND CANCER: A COMPREHENSIVE REVIEW OF MECHANISMS, TYPES, AND THERAPEUTIC STRATEGIES
HTL, 2025
Cancer is a complex and gross disease, which involves the uncontrolled growth of cells in the body and Viral infections are among the major causes of cancer. Some of these viruses are oncoviruses that are responsible for about 15 to 20 percent of all cancers in humans including Human papillomavirus (HPV), Coronavirus (SARS-CoV-2), Epstein Barr virus (EBV), Hepatitis B virus (HBV), Hepatitis C virus (HCV). These viruses can cause carcinogenesis in various ways; for example, by integrating their DNA into the host cell DNA and alter genes' function or by releasing proteins that interfere with cell signaling and cause inflammation that in the course of a long time creates DNA harm. In experimental model, it has been shown that viral DNA is present in tumor tissues, viral genes transform the cells and epidemiological data show association of certain viruses with certain cancers. For instance, while HPV is linked to cervical and anogenital cancers, then HBV as well as HCV is significantly linked to liver cancer. Treatments for these oncoviruses include vaccination (for example HPV, HBV) , antiviral therapy for chronic diseases, immunotherapy for increasing the ability of the host to respond to the virus-infected cells. Further investigation of the molecular events in viral oncogenesis offers a promise for the identification of novel strategies in fighting viral cancers. Knowledge of interaction between viruses and cancer will improve on the management of virus-associated to carcinogenic diseases in the world. This review gives a comprehensive idea on oncovirus, their mechanism on carcinogenesis and therapeutic approaches.
Mechanisms by which DNA tumor virus oncoproteins target the Rb family of pocket proteins
Carcinogenesis, 2003
and the large T antigens of several polyomaviruses. An understanding of these mechanisms may provide further insight into the regulation and functions of Rb family members as well as uncover new targets for the development of novel anti-viral agents, particularly against human papillomavirus, which is a significant cause of human cancer.
Proceedings of the National Academy of Sciences, 2000
Most cervical carcinomas express high-risk human papillomaviruses (HPVs) E6 and E7 proteins, which neutralize cellular tumor suppressor function. To determine the consequences of removing the E6 and E7 proteins from cervical cancer cells, we infected HeLa cells, a cervical carcinoma cell line that contains HPV18 DNA, with a recombinant virus that expresses the bovine papillomavirus E2 protein. Expression of the E2 protein resulted in rapid repression of HPV E6 and E7 expression, followed Ϸ12 h later by profound inhibition of cellular DNA synthesis. Shortly after E6͞E7 repression, there was dramatic posttranscriptional induction of p53. Two p53-responsive genes, mdm2 and p21, were induced with slightly slower kinetics than p53 and appeared to be functional, as assessed by inhibition of cyclin-dependent kinase activity and p53 destabilization. There was also dramatic posttranscriptional induction of p105 Rb and p107 after E6͞E7 repression, followed shortly thereafter by induction of p130. By 24 h after infection, only hypophosphorylated p105 Rb was detectable and transcription of several Rb͞E2F-regulated genes was dramatically repressed. Constitutive expression of the HPV16 E6͞E7 genes alleviated E2-induced growth inhibition and impaired activation of the Rb pathway and repression of E2F-responsive genes. This dynamic response strongly suggests that the p53 and Rb tumor suppressor pathways are intact in HeLa cells and that repression of HPV E6 and E7 mobilizes these pathways in an orderly fashion to deliver growth inhibitory signals to the cells. Strikingly, the major alterations in the cell cycle machinery underlying cervical carcinogenesis can be reversed by repression of the endogenous HPV oncogenes.
Journal of Developmental Biology and Tissue Engineering, 2011
The main goal is connected with providing, on the one hand, of active tumor-suppressor genes for prevention of eventual malignant transformations, and, on the other hand, of functionally active oncogenes for prevention of early aging and death, both in vitro and in vivo. Modulation of an adequate immune control was also necessary, and in this way any eventual unwished side effects from the genetic manipulations applied, could be escaped. Gene transfer in laboratory-cultivated mouse embryonic stem cells (mESCs) was made by use of appropriate recombinant DNA-constructs, which contained the promoter for gene, coding Elongation Factor 1-alpha (EF1-α), isolated from adenoassociated virus (AAV) (Parvoviridae); gene Dcn1, isolated from 3T3 fibroblasts of laboratory mice Balb/c, as well as gene for neomycin resistance, isolated from bacterial DNA-plasmid. Besides those indicated in the scientific literature inactivation of oncogene Dcn1 in the process of normal cell differentiation, its presence in the genome was supported and confirmed by our results from electrophorhesis of genomic DNA from normal mature epithelial cells of adult Balb/c laboratory mice. Furthermore, electrophorhetic profiles of genetic material from wild type (WT) on oncogene Dcn1 and "knock-down" (KD) on it inbred lines experimental mice differed not only on this oncogene, but also on the tumor-suppressor gene HACE1 in both categories of laboratory rodents. Similarly transfected Hela and RIN-5F malignant cells were then in vitro-co-cultivated with myeloid cell precursors, derived from populations of non-transfected laboratory-cultivated mESCs, in the presence of Doxyciclin, known from many literature data as activator of tumor-suppressor genes from STAT-family expression. Our results were also confirmed by the noticed differences in the degree of myeloid differentiation of derived precursor cells in their in vitro-co-cultivation with containing additional copies of tumor-suppressor genes malignant cells from both lines described, in comparison with the data, obtained in their laboratory co-cultivation with non-treated human cervical carcinoma Hela cells. Differences were also observed in in vitro-co-cultivation with the derived by us normal mESCs, containing additional copy of oncogene Dcn1 by the described above transfection with recombinant DNA-constructs. On the other hand, the derived normal cells with inserted additional copy of oncogene Dcn1 have indicated good safety and immunogenity. These cells have also indicated preserved normal cell characteristics, as well as eventual over-expression of the experimentally-activated oncogene Dcn1 in them.